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United States Patent Claims priority, application Japan Aug. 30, 1961 19Claims. (Cl. 260-2395) This invention relates to 16,17-epithiosteroids,and more particularly to 16,17-epithioandrostanes and productionthereof.

It is an object of the present invention to embody 16,17-epithioandrostanes. Another object is to embody androstanes havingpharmacological activities. A further object is to embody a process forconverting 16,17-epoxyandrostanes into l6,l7-epithioandrostanes. Theseand other objects will be apparent to those skilled in the art to whichthis invention pertains from the following description of the generalclass of compounds and certain specific examples of particular membersas well as genoral and specific methods for their production.

The starting materials of the present invention arel6,17-epoxyandrostanes, i.e. l6a,l7a-epoxyandrostanes and16B,l7/3-epoxyandrostanes, having the following partial formula:

tion. The 16,17-epoxyandrostanes include, for instance, the steroidshaving the following specific formula:

wherein X is a-hydroxymethylene, ,B-hydroxymethylene, OL-lOWGlalkanoyloxyrnethylene (e.g. a-acetyloxymethylene,a-propionyloxymethylene, a-butyroyloxymethylene,ot-pentanoyloxymethylene), fi-lower alkanoyloxymethylene (e.g.fi-acetyloxymethylene, fl-propionyloxymethylene,B-butyroyloxyrnethylene, fi-pentanoyloxyrnethylene), carbonyl or loweralkylenedioxymethylene (e.g. ethylenedioxymethylene,trimethylenedioxymethylene), not more than two double bonds may exist inA and/ or B ring and the ripple mark (i) represents Otorti-configuration. More specifically, the 16,17- epoxyandrostanes may beexampled as follows: 3ot-hydroxy-16a,l7a-epoxy-Sfl-androstane,SB-hydroxy-l6a,l7a-epoxydot-androstane, 3a-acetyloxy-16a,l7ca-epoxy-5fi-androstane, 3OC-pl'OpiOl'iYlOXy-16C4,170tepoxy-Sfl-androstane, 3B-butyroyloxy-16a,17a-epoxy-5aandrostane,3-oxo-l6ot,l7wepoxy-5a-androstane, 3-oxo-16oz,17ot-6POXY-5ot2li1dl'05i2lfl6, 3-oxo-16u, l7wepoxy-4-androstene,3-oxo-l6ot,17ot-epoxy-l,4-androstadiene, 3-oxo-16a,l7tt-epoxy4,6-androstadiene, 3,3-ethylenedioxy-l6a, 17 cc epoxy aandrostane, 3,3 ethylenedioxy 16a, 17CC-6POXY-5 (6) -androstene,3,3-ethylenedioxy-l6ct, 170tepoxy-5(6) ,7-androstadiene, 3a-hydroxy-16B,17B-epoxy- 3,123,599 Patented Mar. 3, 1964 5fi-androstane, Sfi-hydroxy-l 65,17B-epoxy-5a-androstane, 3ct-acetylQXy-IQB,17fi-epoxy-5p-androstane, 3 a-propionyloxy-168,l7fi-epoxy-5fi-androstane, 3fi-butyroyloxy-16f3,17fl-epoxy-5ct-androstane, 3-oxo-l6fi,l7fl epoxy-5a-androstane,3-oxo-16B,l7fi-epoxy-5B-androstane, 3-oxo-16fl,175- epoxy-4-androstane,3 -oxol 65, 17 fi-epoxyl ,4-androstadiene, 3 0x0 165,118 epoxy 4,6androstadiene, 3 ,3- ethylenedioxy-16B,17fi-epoxy-5oc-androstane,3,3-ethylenedioxy-l6,l7B-epoxy5 (6) -androstene,3,3-ethylenedioxyl6B,l7B-epoxy-5(6),7-androstadiene, etc. The other 16,l7-epoxyandrostanes may be, of course, equally employed as the startingmaterial. Thus, the following steroids are additionally exampled:3u,llfi-dihydroxy-l6ot,l7u-epoxy- SIS-androstane,SB-hydrOXy-l1-oxo-l6a,l7a-epoxy-5ot-androstane,3,1l-dioxo-l6a,l7a-epoxy-5ot-androstane, 3-ox0- 1 1 ,B-hydroxy-la,l7et-epoxy-4-androstene, 3-oXo-l lB-hydroxyl,17CL-6POXY-1,4-2llldlOSl2ldl6l'lfi, 3,1 1-dioxo-16a,17ot-epoxy-4-androstene, 3 ,1l-dioxo-l6oc,l7a-epoxy-l,4-androstadiene,16a,l7ot-epoxy-5ot-androstane,3,8,l1fi-dihydroxy-165,l7/3-epoxy-5/3-androstane,3,8-hydroxy-11-oxol6B,l7fi-epoxy-5ot-androstane,3,1l-dioxo-16fi,l7fi-epoxy- 5ot-androstane, 3-oxo-1 1 ,B-hydroxy-l6,8,17 ,B-epoxy-4-androstene, 3-oxo-l lB-hydroxyl 6,8, l7B-epoxy-l,4-androstadiene, 3,1l-dioxo-l6fl,l7B-epoxy-4-androstene, 3,1l-dioxo-16p, 1 7B-epoxy-1-,4-androstadiene, 165, l 7;3-epoXy-5u-an drostane,etc.

The conversion of 16,17-epoxyandrostanes into 16,17- epithioandrostanescan be accomplished substantially by three steps represented by thefollowing partial formula:

R Step III D wherein R is an acid radical such as halogen (e.g.chlorine, bromine), lower alkanoyloxy (e.g. acetyloxy, propionyloxy,butyroyloxy, pentanoyloxy), benzoyloxy, lower alkanesulfonyloxy (e. g,methanesulfonyloxy, ethanesulfonyloxy) benzenesulfonyloxy and loweralkylbenzenesulfonyloxy (e.g. toluencsulfonyloxy, xylenesulfonyloxy). Ofthese steps, the first step per so has been disclosed in US. Patent No.2,982,777 and is not included in the present invention. However, thestep will be hereinafter illustrated for convenience as well as theother two steps. When any radical of the starting 16,17-epoxyandrostaneis undesirably alfected by the reagent employed in any step, suchradical is required to be protected in a conventional manner prior tothe execution of the reaction in such step. However, whether theprotection is needed will be obvious to those skilled in the art.

In the first step, the 16,17-epoxyandrostanes are subjected to thefission of epoxy linkage with thiocyanic acid. The reaction may becarried out by introducing thiocyanic acid gas produced by aconventional method [I-I. Buck et al.: Z. anorg. Chem, 77, 51 (1912)]into a solution of the 16,17-epoxyandrostane in a suitable solvent (e.g.benzene, carbon disulfide, dichloromethane, chloroform, carbontetrachloride, ether) or adding the 16,17-epoxyandrostane to a solutionof thiocyanic acid prepared in advance by shaking a salt of thiocyanicacid (e.g. sodium thiocyanate, potassium thiocyanate) with an acid (e.g.phosphoric acid) in a suitable solvent (e.g. benzene, carbon disulfide,dichloromethane, chloroform, carbon tetrachloride, ether, dioxane),followed by allowing the resultant mixture to stand at room temperatureto 25 C.) or heating the same on a water-bath. Generally speaking, ittakes a relatively long time for completion of the reaction and,therefore, excess of thiocyanic acid may be preferably employed.

In the second step, the resulting thiocyanatohydrines are subjected tothe acylation with an organic or inorganic acylating agent such ashalogenating agent (e.g. thionyl chloride, thionyl bromide, phosphorusoxychloride, phosphorus trichloride, phosphorus tribromide, phosphoruspentachloride), lower alkanoylating agent (e.g. acetyl chloride,propionyl chloride), benzoylating agent (e.g. benzoyl chloride, benzoylbromide), lower alkanesulfonylating agent (e.g. methanesulfonylchloride, ethanesulfonyl chloride), benzenesulfonylating agent (e.g.benzenesulfonyl chloride, benzenesuifonyl bromide) and loweralkylbenzenesulfonylating agent (e.g. toluenesulfonyl chloride,xylenesulfonyl chloride). Although any of the said acylating agents canbe equally well employed, the use of lower alkanesulfonylating agent orlower alkylbenzenesulfonylating agent is preferred. When these preferredagents are employed, the reaction can be accomplished by treating thethiocyanatohydrine with the acylating agent in the presence of acondensing agent (e.g. pyridine, picoline, triethylamine) at roomtemperature 10 to 25 C.) or While ice-cooling.

In the third step, the resulting acylated thiocyanatohydrines aresubjected to the formation of epithio linkage with a basic agent. As thebasic agent, there may be employed alkali metal hydroxide (e.g. sodiumhydroxide, potassium hydroxide), alkaline earth metal hydroxide (e.g.calcium hydroxide, barium hydroxide), alkali metal hydride (e.g. lithiumaluminum hydride, lithium borohydride, sodium borohydride) and the like.The reaction can be performed by heating the acylated thiocyanatohydrinewith the said basic agent in a suitable solvent (e.g. methanol, ethanol,ether, tetrahydrofuran, dioxane), if necessary, While refluxing.Although the reaction can proceed at room temperature (10 to 25 C.), ittakes usually a long time for completion of the reaction.

The final products are the 16,17-epithioandrostanes, i.e.16a,17ot-epithioandrostanes and 166,176-epithioandrostanes, having thefollowing partial formula:

wherein the ripple mark (2) represents OL- or 6-configuration. The16,17-epithioandrostanes include, for instance, the steroids having thefollowing specific formula:

wherein X has the same significance as designated above, not more thantwo double bonds may exist in A and/or B ring, and the ripple mark (5)represents 06- or 6- configuration. More specifically, the16,17-epithioandrostanes may be exampled as follows:

3 OC-llYdl'OXY-l6/3,17BEPlthlO-Sfl-al'ldIOStal'l, 36-hydroxy-166,17/3-epithio-5 a-androstane, 3ot-acetyloxy-16/3,176-epithio-56-androstane, 3a-propionyloxy-166,17/3-epithio-5/3-androstane,36-butyroyloxy-16/3,176-epithio-Sea-androstane,3-oxo-166,176-epithio-5u-androstane,3-oxo-166,17/3-epithio-56-androstane,3-oxo-16/3,176-epithio-4-androstene,3-oxo-166,176-epithio-1,4-androstadiene,3-oxo-16/3,17/3-epithio-4,6-androstadiene,3,3-ethylenedioxy-166,176-epithio-Sa-androstane, 3,3-ethylenedioxy-166,17/3-epithio5(6) -androstene, 3,3-ethylenedioxy-l66,176-epithi0-5 (6) ,7-androstadiene, 3a-hydroxy-16ot,17a-epithio-56-androstane,36-hydroxy-16m,17a-epithio-5a-androstane, 3:x-acetyloxy-16u,17a-epithio-56-androstane, 3ot-propionyloxy-16u,17a-epithio-5/3-androstane,36-butyroyloxy-16a,17a-epithio-5a-androstane, 3-OXO-16OL,17a-epithio-5a-androstane, 3 -oxo-16a,17ot-epithio-56-androstane,3-oxo-16u,17a-epithio-4-androstene,3-oxo-16a,17a-epithio-1,4-androstadiene,3-oXo-16oc,17oz-epithio-4,6-androstadiene,3,3-ethylenedioxy-16a,17vc-epithio-5a-androstane, 3,3-ethylenedioxy-16a,17a-epithio-5 (6) -androstene, 3,3-ethylenedioxy-l6rx,17ot-epithio-5 (6) ,7-androstadiene, etc.

There may be also obtained the other 16,17-epithioandrostanescorresponding to the starting 16,17-epoxyandrostanes, provided that theconfiguration of the epoxy group is reversed. Thus, the followingsteroids may be additionally exampled:

3 a,11/3-dihydroxy-16/3,176-epithio-56-androstane,

3 6-hydroxy-1 1-oxo-16/3,17/3-epithio-Sa-androstane,

3,1 1-dioxo-166,176-epithio-4-androstene,

3 -0xo-1 16-hydroxy-16/3,176-epithio-1,4-androstadiene, 3,1l-dioxo-166,176-epithio-4-androstene,3,11-dioxo-16/3,176-epithio-1,4-androstadiene,166,17/3-epithio-Sa-andrcstane,36,116-dihydroxy-16ot,17a-epithio-56-androstane,

3 6-hydroxy-1 1-OX0-16C6, 17a-epithio-Sea-androstane,3,1l-dioxo-l6a,17ot-epithio-5ot-androstane,

3-oxo-1 l/3-hydroxy-l6ot,17a-epithio-4-androstene, 3-oxo-116-hydroxy-16a,17oz-epithio-1,4-androstadiene,3,1l-dioxo-l6a,17a-epithio-4-androstene,

3 ,11-dioxo-16oz,17a-epithio-1,4-androstadiene,16a,17a-epithio-5a-androstane, etc.

These 16,17-epithioandrostanes are characterized by showing anti-DOCA(desoxycorticosterone acetate) activity in general. For instance,3-oxo-166,17/3-epithio-4-androstene,3-oxo-16/3,176-epithio-1,4-androstadiene, 3-oxo-166,176-epithio-4,6-androstadiene and 3 6-hydroxy-1 66,176-epithio-5oc-androstane each shows the significant inhibition of theresponse caused by 10 micrograms of DOCA, when administeredsubcutaneously at a dose of 5 milligrams or less per rat weighing fromto grams. Thus, the 16,17-epithioandrostanes are useful as anti-DOCAagents.

The following examples set forth illustratively pres ently-preferredembodiments of the invention.

In the examples the abbreviations have the following significances: mg.milligram(s); g., grarn(s); ml., millilitre(s); Anal. Calcd., analysiscalculated; and C., degrees Centigrade. Other abbreviations haveconventional significances.

Example 1 do rd -93 .03

dd Fl? To an ethereal solution of thiocyanic acid prepared frompotassium thiocyanate (45 g.), phosphoric acid (45 g.) and ether (150ml.), there is added 3-oxo-16a,17ot-epoxy- 4-androstene [H. Heusser etal.: Helv. Chim. Acta, 33, 2242 (1950)] (4.15 g.), and the resultantsolution is allowed to stand overnight at room temperature 15 to 20 C.)The reaction mixture is washed with Water, sodium carbonate and water inturn, and dried over anhydrous sodium sulfate. Removing the ether, theresidue is dissolved in acetone (100 ml), treated with decolorizingcarbon and then concentrated to give3-oxo-16fi-thiocyanato-l7rx-hydroxy-4-androstene (3.88 g.) as cubiccrystals melting at 190 to 192 C. (decomp).

Anal. Calcd. for (3 13 0 1515: C, 69.53; H, 7.88; N, 4.05; S, 9.28.Found: C, 69.30; H, 7.90; N, 4.31; S, 9.18.

To a solution of 3-oxo-16B-thiocyanato-l7a-hydroxy- 4-androstene (2.908g.) in pyridine (24 ml.), there is gradually added methanesulfonylchloride (3.0 g.) while cooling at 0 C., and the resultant solution isallowed to stand overnight at the same temperature. The reaction mixtureis mixed with ice-water (30 m1.) and shaken With benzene. The benzeneextract is washed with 10% hydrochloric acid, water, 10% sodiumcarbonate and water in turn, and dried over anhydrous sodium sulfate.The solvent is removed to give crude3-oxo-16fi-thiocyanato-17amethanesulr'onyloxy-4-androstene (3.56 g.) asa yellow viscous substance.

To a solution of the above-prepared crude 3-oxo-16B-thiocyanato-17a-methanesulfonyloxy-4-androstene (3.56 g.) intetrahydrofuran (10 ml.), there is added a solution of potassiumhydroxide (4 g.) in ethanol (40 ml.) while boiling in nitrogen stream,and the resultant solution is boiled for 2 hours in nitrogen stream.After cooling, the reaction mixture is mixed with water and shaken withbenzene. The benzene extract is washed with water, dried over anhydroussodium sulfate and concentrated to give the residue (2.735 g.), which iscrystallized from ether to give 3-oxo-16,6, 17B-epithio-4-androstene(2.012 g.) as crude crystals.

Example 2 (I? [ZQU 1 l A mixture of3-oxo-16,8-thiocyanato-17a-hydroxy-4- androstene (5.65 g.) prepared asin Example 1, ethyleneglycol (400 ml.) and p-toluenesulfonic acid (300mg.) is gradually distilled at a temperature between 72 and 73 C. under3 mm. Hg, whereby the crystals of the starting material are graduallydissolved and the fine needles crystallized out. The reaction mixture isconcentrated to about A volume in 4 hours. The concentrate is cooled,mixed with sodium carbonate and water, and filtered. The collectedcrystals are Washed with water, dried and recrystallized from methanolto give 3,3-ethylene-dioxy-16B- thiocyanato-17a-hydroxy-5-androstene(5.50 g.) as crystals melting at 190 to 192 C. (decomp) Anal. Calcd. forC H O NS: C, 67.83; H, 8.02; N, 3.60; S, 8.23. Found: C, 67.97; H, 8.08;N, 3.41; S, 8.28.

To a solution of 3,3-ethylenediox-16[3-thiocyanatol7ct-hydroxy-5-androstene (1.582 g.) in pyridine (35ml.), there is added methanesulfonyl chloride (2.2 g.) whileice-cooling, and the resultant solution is allowed to stand for 2 hourswhile ice-cooling and then overnight at room temperature (15 to 20 C.).Adding ice-water to the reaction mixture, the precipitate is collectedby filtration and dried to give the solid (1.810 g. which iscrystallized from a mixture of dichloromethane and acetone to give 3,3-ethylenedioxy-l6B-thiocyanato 17a-methanesulfonyloxy- S-androstene(1.604 g.) as needles melting at 189 to 190 C. (decomp).

Anal. Calcd. for C H O NS C, 59.07; H, 7.11; S, 13.71. Found: C, 59.17;H, 7.16; S, 13.46.

A solution of3,3-ethy1enedioxy-16B-thiocyanato-17amethanesulfonyloxy-S-androstene(2.00 g.) in a mixture of potassium hydroxide (2 g.), methanol (20 ml.)and ethanol (20 ml.) is refluxed for 1 hour and concentrated to /2volume. Adding water to the reaction mixture, the precipitate iscollected by filtration, dried and crystallized from a mixture ofdichloromethane and acetone to give3,3-ethylenedioxy-16,8,17B-epithio-5-androstene (1.263 g.) as needlesmelting at 202 to 204 C. (decomp).

Anal. Calcd. for C H O S: C, 72.78; H, 8.73; S, 9.25. Found: C, 72.50;H, 8.73; S, 9.04.

A mixture of 3,3-ethylenedioxy-165,17B-epithio-5- androstene (1.263 g.)in acetone (50 ml.) and p-toluenesulfonic acid mg.) is refluxed for 1hour. Adding water to the reaction mixture, the precipitate is collectedby filtration and crystallized from a mixture of methanol and water togive 3-oxo-16/3,l7fi-epithio4-androstene (1.00 g.) as prisms melting at171 to 173 C.

Anal. Calcd. for C H OS: C, 75.44; H, 8.66; S, 10.60. Found: C, 75.43;H, 8.73; S, 10.67.

Example 3 no CHaCOO on ()fi CHsOOO 9S 020113 Tm orncoo- .J

IZI

ll? CH3COO Q To an ethereal solution of thiocyanic acid prepared frompotassium thiocyanate (30 g.), phosphoric acid (45 g.) and ether (150ml.), there is added 3fi-acetyloxy- 16a,17a-epoxy-5a-androstane [1.Fajkos et al.: Collection Czechoslov. Chem. Communs, 20, 312 (1955)](5.00 g.), and the resultant solution is allowed to stand overnight atroom temperature to C.). The reaction mixture is washed with water, 10%sodium carbonate and Water in turn, and dried over anhydrous sodiumsulfate. Removing the ether, the residue is crystallized from a mixtureof acetone and hexane to give 3fl-acetyloxy-16B-thiocyanato-17a-hydr0xy-5a-androstane (5.32 g.) aspillars melting at 193 to 195 C.

[m] -27.8:2 (c.=1.054 CHCl Anal. Calcd. for C H O NS: C, 67.48; H, 8.50;N, 3.58; S, 8.19. Found: C, 67.64; H, 8.61; N, 3.57; S, 8.10.

To a solution of3/3-acety1oxy-16,8-thiocyanato-17othydroxy-Sa-androstane (5.12 g.) inpyridine (60 ml.), there is added methanesulfonyl chloride (5.1 g.), andthe resultant solution is allowed to stand overnight in a rec.)frigerator (0 C.). The reaction mixture is mixed with ice-water (50 ml.)and shaken with ether. The ether extract is washed with 10% hydrochloricacid, water, 10% sodium carbonate and water in turn, and dried overanhydrous sodium sulfate. Removing the solvent, the residue iscrystallized from a mixture of ether and petroleum ether to give3B-acetyloxy-16fi-thiocyanato-17amethanesulfonyloxy-5u-androstane (5.71g.) as needles melting at 145 to 147 C. (decomp).

Anal. Calcd. for C H O NS C, 58.82; H, 7.51; N, 2.98; S, 13.66. Found:C, 58.93; H, 7.75; N, 2.79; S, 13.76.

To a solution of potassium hydroxide (5 g.) in ethanol (50 1111.), thereis added3,8-acetyloxy-l6B-thiocyanato-17a-mehanesulfonyloxy-5a-androstane (5.25g.), and the whole solidified is dissolved by adding water 15 ml.) 30minutes thereafter. The resulting solution is refluxed for 1 hour, andthen mixed with water (15 ml).

The reaction mixture is shaken with dichloromethane. The dichloromethaneextract is washed with water, dried over anhydrous sodium sulfate andthe solvent removed. The residue is crystallized from methanol to givecrude crystals (3.03 g.) melting at to C. The crude crystals aredissolved in pyridine (10 ml.) and acetic anhydride (5 ml.) and heatedfor 1 hour on a water bath. Treating the reaction mixture according to aconventional manner, the residue is chromatographed on alumina II (30g.) and the eluate from a mixture of petroleum ether and benzene (1:1)is crystallized from a mixture of ether and methanol to give3B-acety1oxy-16Q,17B-epithio-5aandrostane (2.668 g.) as prisms meltingat to 137 C.

[a] +55.5i2 (c.=1.010 CHC1 Anal. Calcd. for C H O S: C, 72.36; H, 9.25;S, 9.20. Found: C, 72.60; H, 9.35; S, 8.85.

To a solution of potassium carbonate (2.2 g.) in 80% methanol (50 m1.),there is added 3fi-acetyloxy-16,B,17,B- epithio-5ot-androstane (2.668g.), and the resultant solution is refluxed for 2 hours. Adding water tothe reaction mixture, the precipitate is collected by filtration, washedwith water and recrystallized from a mixture of dichloromethane andmethanol to give 3fi-hydroxy-16fi,17B-epithio-5a-androstane (2.06 g.) asscales melting at 146 to 148 C.

Anal. Calcd. for C H OS: C, 74.45; H, 9.87; S, 10.46. Found: C, 74.30;H, 9.92; S, 10.38.

To an ethereal solution of thiocyanic acid prepared from potassiumthiocyanate (11.5 g.), phosphoric acid (18.7 g.) and ether (70 m1.),there is added 3-OXO-16oc,l7otepoxy-Su-androstane (1.795 g.), and theresultant solution is allowed to stand overnight at room temperature (15to 20 C.). The reaction mixture is washed with Water, 10% soduimcarbonate solution and water in turn, and dried over anhydrous sodiumsulfate. Removing the solvent, the residue is crystallized from amixture of acetone and hexane to give3-oxo-16fi-thiocyanato-17ahydroxy-5a-androstane (1.885 g.) as needlesmelting at 209 to 211 C.

[u] -3.4:2 (c.=0.996 CHC13).

Anal. Calcd. for C H O NS: C, 69.12; H, 8.41; N, 4.03; S, 9.23. Found:C, 69.53; H, 8.36; N, 3.90; S, 9.15.

To a solution of 3-oxo-1fifi-th-iocyanato-17ot-hydroxy- SOt-andrQstane(1.768 g.) in pyridine (30 ml), there is added methanesulfonyl chloride(1.8 g.), and the resultant solution is allowed to stand overnight in arefrigerator C.). Adding ice-water (20 ml.) to the reaction mixture, theresulting mixture is shaken with ether. The ether extract is Washed with10% hydrochloric acid, water, 10% sodium carbonate and Water in turn anddried over anhydrous sodium sulfate. Removing the solvent, the residueis collected by filtration and crystallized from a mixture of acetoneand hexane to give 3-oxo-165-thiocyanato17amtethanesulfonyloxy-Sa-androstane (1.879 g.) as needles melting at134 to 135.5 C.

Anal. CalCd. for C21H31O4S2NZ C, H, N, 3.29; S, 15.07. Found: C, 59.33;H, 7.51; N, 3.20; S, 15.11.

To a solution of3-oxo-16B-thiocyanato-Hot-methanesulfonyloxy-Sot-androstane (1.777 g.)in tertahydrofuran (30 ml.), there is added a solution of potassiumhydroxide (3 g.) in a mixture of methanol (20 ml.) and ethanol (20 ml),and the resultant solution is refluxed for 1 hour. The reaction mixtureis mixed with water and shaken with dichloromethane. The dichloromethaneextract is Washed with Water and dried over anhydrous sodium sulfate.Removing the solvent, the residue is chromatognaphed on alumina (20 g.).The eluate from a mixture of petroleum ether and benzene (1:1) iscrystallized from ether and recrystallized from acetone to give3-oxo-16B, 17fi-epithio-5ct-androstane (403 mg.) as needles melting at173 to 175 C. The mother liquor of crystallization \is combined togetherwith that of recrystallization and chromatographed an alumina (20 g.).The eluate from a mixture of petroleum ether and benzene (9: 1) iscrystallized from ether and recrystallized from acetone to giveadditional crystals (240 mg.) of 3-oxo-16fi,17B-epithio-Sa-al'ldIOStQJlB.

M1 +101.6i2 (c.=1.019 CHCl Anal. Calcd. for C H OS: C, 74.94; H, 9.27;S, 10.53. Found: C, 74.90; H, 9.32; S, 10.49.

The starting material of this example, 3-oxo-16a-17uepoxy-5a-androstane,is prepared by treating 3B-hydroxy- 16m,17Ct-SPOXY-5OL-flfit'll'08t8l'l6[1. Fajkos et al.: Collection Czechoslov. Chem. Communs, 20, 312 (1955)]with chromic acid in pyridine at room temperature.

Example 5 Example 6 so so -9; -93

h on ti 9 to According to the same manner as described in Example 1,3-oxo-16a,17a-epoxy-4,6-androstadiene is converted into 3 oxo16/3,17fl-epithio-4,6-androstadiene through 3oxo-16B-thiocyanato-l7u-hydroxy-4,6-androstadiene and3-oxo-16fl-thiocyanato-17ot-methanesulfonyloxy-4,6-androstadiene.

3-oxo-16B,17,6-epithio-4,6-androstadiene is obtained as prisms meltingat 204 to 205 C.

Anal. Calcd. for C H OS: C, 75.95; H, 8.05; S, 10.67. Found: C, 76.11;H, 8.09; 5, 10.79.

The starting material of this example, 3-OXO-160L,170L-epoxy-4,6-androstadiene, is prepared by refluxing 3-oxo-16a,17a-ep0xy-4-androstene with chloranil (tetrachlorop-benzoquinone) int-butanol.

SON

Example 7 ifi CHaCOO I S CN PW CHsCOO s ON (\QOSO2CH3 onto 00- I A onof? Q3 Q3 Ms "M PU l S; m

on on I/\lfi sQN '/\1fiSCN AI /\l l X on on I SON Ali- O /\l 1 r l andon wil AQ/ 'Y wherein X is a member selected from the group consistingof a-hydroxymethylene, ;3-hydroxymethy1ene, onloweralkanoyloxymethylene, fl-lower alkanoyloxymethylene, carbonyl and loweralkylenedioxymethylene, X being lower alkylenedioxymethylene only whenring A is saturated, Y is a member selected from the group consisting ofa-hydroxymethylene, B-hydroxymethylene, 06- lower alkanoyloxyrnethylene,fi-lower alkanoyloxymethylene, and lower alkylenedioxymethylene, and Ris a member selected from the group consisting of lower alkanesulfonyland lower alkylbenzenesulfonyl. 12. 3oxo-l6fi-thiocyanato-l7u-methanesulfonyloxy- 4-androstene.

13. 3,3 ethylenedioXy-l6,8-thiocyanato-17a-methanesulfonyloxy-S (6-androstene.

14. 3B acetyloxy 16;?thiocyanato-17a-methanesulfonyloxy-M-androstane.

15. 3 x0-IGfl-thiocyanato-l7a-methzmesulfonyloxy- Sa-andrOstane.

16. 3 0x0-16,8-thiocyanato-17a-methanesulfonyloxy- 1,4-androstadiene.

17. 3 0x0-16,8-thiocyanato-l7a-methanesulfonyloxy- 4,6-androstadiene.

18. A member selected from the group consisting of compounds of theformulae S GN and

S CN

wherein X is a member selected from the group consisting ofa-hydroxymethylene, ,B-hydroxyrnethylene, alower alkanoyloxymethylene,B-lower alkanoy-loxymethylene, carbonyl and loweralkylenedioxymethylene, X being lower alkylenedioxymethylene only whenring A is saturated, Y is a member selected from the group consisting ofa-hydroxymethylene, ,B-hydroxymethylene, alower alkanoyloxymethylene,B-lower alkanoyloxymethylene, and lower alkylenedioxymethylene, and R isa member selected from the group consisting of lower allcanesulfonyl andlower tal'kylbenzenesuilfonyl.

19. 3B acetyloxy-I6Q-methanesulfonyloxy-17a-thiocyanato-h-androstane.

References Cited in the file of this patent UNITED STATES PATENTS2,982,777 Loechel et a1. May 2, 1961

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULAE